17-substituted 14beta-estr-4-enes



United States Patent 3,338,925 17-SUBSTITUTED 14,8-ESTR-4-ENES John H. Fried, Palo Alto, Calif., .assignor to Syntex Corporation, Panama, Panama, a corporation of Panama No Drawing. Filed Oct. 25, 1965, Ser. No. 505,194

14 Claims. (Cl. 260397.4)

The present invention is directed at cyclopentanopolyhydrophenanthre'ne derivatives, specifically to 14,8-estr-4- ones of the formula:

wherein By the term (lower) alkyl, and derivations thereolf such as (lower)alkeny1 and (lower) alkynyl is intended a branched or straight chain hydrocarbon group of six or less carbon atoms. In the case of olefinic groups, such will contain at least two carbon atoms. Representations of such (lower) alkyl groups are thus methyl, ethyl,- propyl, butyl,-pentyl and hexyl;-of such (lower)alkynyl groups are vinyl, propargyl and the like; and of such (lower) alkynyl groups are ethynyl, propynyl and the like.

The-hydrocarbon carboxylic acyl and acyloxy groups of the present invention will contain less than 12 carbon atoms and may be of a straight, branched, cyclic or cyclicaliphat-ic chain structure. These may be saturated, unsaturated or aromatic and optionally substituted by functional groups such as hydroxy, alkoxy containing up to 5 carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino, halogeno and the like. Typical esters thus include acetate, propionate, enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate, cyclopentylpropionate, aminoacetate, B-chloropropionate, adamantoate and the like.

The compounds of this invention demonstrate hormonal properties, primarily androgenic activity, associated with anabolic activity. Certain of these derivatives, most 'notably those wherein R is ethynyil or chloroethynyl, possess progestat-ional activity and are useful in the control of fertility.

In the synthesis of the 14,B-estr-4-enes, a 3-methoxy-l8- methyl-l4fl-estra-1,3,5 ()-trien-17-one or 3 methoxy- 14 3- estra-1,3,5 (10)-trien-17-one is utilized as the starting material. The preparation of these starting materials is in part the subject matter of copending application Ser. No. 505,191, filed Oct. 25, 1965, and is described in detail therein.

According to the present invention, these starting materials are reduced with sodium or lithium in liquid amm-onia to yield 3-methoxy-18-methyl-14B-estra 2,5(10)- 3,338,925 Patented Aug. 29, 1967 "ice dien-l7a-ol and 3-methoxy-14fi-estra-2,5 10) -dien-17a-ol respectively. These com-pounds may be treated with acid, such as methano lic hydrochloric acid, to eifect hydrolyti'c rearrangement, thus generating 17a-hydroxy-l8-methyl- 14/3-estr-4-en-3-one and l7a-hydroxy-14B-est-r-4-en 3- one, respectively.

Alternatively the 3-methoxy-18-methyl-14fi-estra 2,5 (l0)-dien-17a-ol or 3-methoxy-14 3-estra-2,5(l0) dien- 17a-olor 3-methoxy-14B-estra-2,5(10)-dien-17a 01 are oxidized, as by an Oppenauer oxidation, to yield 3-methoxy-l8-methyl-14,8-estra-2,5(10)-dien-17-one or 3 meth- 0Xy-14,Bestra2,5( 10)-dien-17-o'ne respectively. These 17- keto intermediates are then ethynylated in the Uri-position through the action of lithium acetylide or may be substituted in the use of the appropriate Grignardreagents, e.-g., methylimagnesi-umbromide, ethynylmagnesiurn bromide or the like. 17}8-alkenyl derivatives, such as vinyl compounds, are preferably obtained from the correspond ing 17B-alkynyl compound through controlled hydrogenation. Upon further hydrogenation, the corresponding 7B- alkyl derivative is obtained. l7fi-cyclopropyl derivatives are obtained from the corresponding 17,3-vinyl intermediate via the action of methylene iodide and zinc-copper couple.

After introduction and elaboration of 17fl-substituents, the 3-methoxy-A A-ring system is hydrolyzed and rearranged through treatment with acid, as previously described, to yield the corresponding 3-keto-A -system. Use of a weak acid alternatively yields the 3-keto-A -system which is substantially equivalent in this particular class of compounds.

Esterificatio'n of a secondary 17a-hydroxy group is accomplished in the usual manner with an acylation agent such as acetic anhydride or oaproic anhydride. Tertiary 17w-hydroxy groups are similarly esterified with an acylating agent in the presence of the corresponding acid and a strong acid such as p-toluenesulfonic acid.

Formation of l7a-tetrahydropyranyloxy ethers is realized through the action of dihydropyran on the free chydroxy group in the presence of an acid such as ptoluenesulfonic acid.

Reduction of a 3-keto 14,B-estr-4-ene of the present invention, as with sodium borohydride or lithium aluminum hydride in tetrahydrofuran yields the corresponding 3/8- hydroxy-l4fl-estr-4-ene which may be acylated as with an acid anhydride in pyridine or alternatively converted to the 3fi-tetrahydropyranyl ether with dihydro'pyran in the presence of an acid.

' The following examples will serve to further typify the nature of this invention but should not be construed as a limitation on the scope thereof.

Example 1 A mixture of 8 g. of 3-rnethoxy-l8 -methylestra=l,3,5- (10)-trien-17-one, 10 ml. of ethyl orthoformate, 5 ml. of ethylene glycol and 300 mg. of p-toluenesulfonic acid is refluxed under nitrogen for two hours and then poured into methylene chloride. The organic solution is washed with aqueous sodium bicarbonate solution, dried, treated with 0.5 ml. of pyridine and concentrated in vacuo. The resultant oil is triturated with petroleum ether and allowed to solidify to yield 3-methoxy-17,17-ethylenedioxyl8-methylestra-11,3,5 (10)-triene. To a solution of this material (5.66 g.) in 250 ml. of tetr-ahydrofuran are added 1 equivalent (5.45 .g.) of pyridine hydrobromide per-bromide. After stirring for 2 /2 hours at room temperature,

sium t-butoxide (obtained by adding 2.62 g. of potassium metal to t-butanol). The mixture is poured into water and extracted with methylene chloride. These extracts are washed with water, dried over sodium sulfate, and evaporated to dryness. The residue is combined with 130 ml. of methanol and 7.2 ml. of 2 N hydrochloric acid and this mixture is refluxed under nitrogen for 5 hours. The solution is then diluted with methylene chloride, washed with dilute aqueous sodium bicarbonate solution, dried over sodium sulfate and evaporated in vacuo. The residue is dissolved in petroleum ether containing a little benzene and chromatographed on silica, eluting with 1:9 ethyl ether: petroleum ether to yield 3-methoxy-l8-methylestral,3,5(l),14-tetraen-l7-one. This material is dissolved in 25 ml. of ethyl acetate and hydrogenated in the presence of 7 g. of prereduced 10% palladium-on-charcoal in 475 ml. of ethyl acetate, at room temperature and atmospheric pressure. The hydrogenation is continued until the theoretical amount of hydrogen is absorbed and the catalyst is then removed by filtration, washing the solid well with methylene chloride. The combined washings and filtrates are then evaporated to yield 3-methoxy-l8-methyl-14B-estra-1,3,5(l0)-trien-l7-one which may be further purified through recrystallization from acetonezpetroleum ether.

In a similar fashion from 3-methoxyestra-l,3,5(10)- trien-l7-one, there is obtained 3-methoxy-l4-B-estra-l,3,- -trien-l7-one.

Alternatively these compounds may be obtained through treatment of the 17-keto starting material with isopropenyl acetate and p-toluenesulfonic acid to yield the A -ene-17-acetate. Upon treatment of this enol acetate with chlorine or bromine, the corresponding l6-chlorol7-keto or 16-bromo-17-keto compound is obtained. Upon prolonged refluxing of a mixture of either of these compounds, ethylene glycol and p-toluenesulfonic acid or dinitrobenzenesulfonic acid in toluene, the 16-chloroor l6-bromo-17,17-ethylenedioxy intermediate is obtained which may be dehydrohalogenated and hydrogenated as previously described.

Example 2 One gram of 3-methoxy-18-methyl-14l3-estra-1,3,5( 10)- tr-ien-l7-one is suspended in 30 ml. of t-butanol, 30 ml. of tetrahydrof-uran and 150 ml. of liquid ammonia. Sodium metal is then added until the reaction mixture acquires a blue color and this color is maintained for 7 hours by the addition of sodium as necessary. At the end of this time, suflicient methanol is added to discharge the blue color and the ammonia is then removed through evaporation. After the cautious addition of water, the solution is extracted under nitrogen with methylene chloride. The extracts thus obtained are washed with water, dried over sodium sulfate, and evaporated to dryness to yield 3-methoxy-l8-methyl-14B-estra-2,5-(l0)-dien-17ix- 01.

A solution of 2.3 g. of 3-methoxy-18-methyl-14B-estra- 2,5(10)-di611l70t-01 in 60 ml. of toluene and 60 ml. of cyclohexanone is dried by removing ml. of solvent by distillation. A solution of 1.6 5 g. of aluminum isopropoxide in 7 ml. of anhydrous toluene is then added and the mixture refluxed for 8 hours. The mixture is dilute-d with water and extracted with ethers. These extracts are evaporated and the residue is diluted with water, flushed with nitrogen and distilled. The residue is extracted several times with methylene chloride and these extracts, after washing with Water and drying over sodium sulfate, are evaporated to dryness to yield B-methoxy-18-methyl-145-estra-2,5( l0) -dien-l7-one.

Example 3 p A stream of dry, acetone-free acetylene is introduced under nitrogen into a cooled mixture of dry tetrahydrofuran and 88 ml. of a 15.1% solution of n-butyl' lithium in hexane. One gram of 3-rnethoxy-l8-methyl-14B-estra- 2,5(10)-dien-17-one, dissolved in a small amount of tetrahydrofuran is then added. After the mixture has stood at room temperature for 24 hours, one-half the above quantity of lithium acetylide, prepared in the same fashion is added. This mixture is allowed to stand at room temperature for a further 24 hours and is then cautiously poured into a stirred ice-water mixture. This is extracted with methylene chloride and the extracts in turn are washed with water, dried and evaporated to dryness. The residue is chromatographed on silica using 5% isopropyl alcohol in chloroform to yield 3-methoxy-17,8-ethynyl-l8- methyl-l4fi-estra-2,5 (10)-dien-17a-ol.

One gram of 3-methoxy-17B-ethynyl-l8-methyl-l4l8- estra-2,5*(10)-dien-17ot-ol in 25 ml. of methanol and 4 ml. of 2 N aqueous hydrochloric acid is heated at reflux for 30 minutes under nitrogen. At the end of this time, the cooled reaction mixture is neutralized with sodium bicarbonate and extracted with methylene chloride. These extracts are Washed with Water, dried over sodium sulfate and evaporated to yield 17 a-hydroxy-17B-ethynyld8-methyl-14/3-estr-4-en-3-one.

By utilizing 3-methoxy-'14,8-estra-2,5(10)-dien-17-one in the procedure of this example, there is obtained 170chydroxy-17 B-ethynyl-l4 3-estr-4-en-3-one as the final compound.

By employing oxalic acid in the foregoing procedure, the corresponding 14B-estr-5(l0)-enes are obtained.

Example 4 A solution of 5 g. of 3-methoxy18-methy1-14B-estra- 2,5(l0)-dien-l7-one in 250 ml. of thiophene-free benzene is treated with 27.5 ml. of 4 N methylmagnesium bromide in anhydrous ether. The mixture is heated at reflux under anhydrous conditions for 3 hours, cooled, and cautiously treated with excess aqueous ammonium chloride solution. This mixture is then extracted with ethyl acetate and these extracts are in turn washed with water, dried over sodium sulfate and evaporated to dryness to yield 3-methoxy-17,8,18-dirnethyl-14fi-estra-2,5 (10)-dien 17a 01, which is recrystallized from methylene chloridezhexane. By refluxing this compound in methanolic hydrochloric acid as described in Example 3, there is obtained 17ahydroxy-17B,18-dimethyl-l4fi-estra-4-en-3-one.

Likewise by subjecting 3-methoxy-14B-estra-2,5(10)- dien-17-one to the procedure of this example, there is obtained 17a-hydroxy-17fi-methyl-14B-estr-4-en-3-one.

Example 5 A solution of 8.5 g. of 1,2-dichloroethy1ene in 50 ml. of anhydrous ether is added in a dropwise fashion, under nitrogen and at 0 C. over a 30 minute period to a stirred solution of 15 ml. of 1.4 N methyl lithium in anhydrous ether. After stirring for an additional minutes at room temperature, a solution of 0.5 g. of 3-methoxy-18-methyl- 146-estra-2,S(10)-dien-l7-one in 20 ml. of anhydrous ether is added in a dropwise fashion with stirring over a 15 minute period. Stirring at room temperature is continued for 18 hours, and the reaction mixture is then poured into ice water and extracted with ether. These extracts are washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on alkaline alumina with 8:2 hexane: ether to yield 3-methoxy-17fl-chloroethynyl-18-methyl- 14fl-estra-2,5(10)-dien-17a-ol, which may be recrystallized from methanol. This compound is hydrolytically rearranged with methanolic hydrochloric acid as described in Example 3 to yield 17u-hydroxy-l7/3-chloroethynyl-18- methyl-l4B-estr-4-en-3-one.

l7a-hydroxy-17(3-chloroethynyl-l4,B-estr-4-en-3-one is obtained in the same manner from the analogous starting material.

Example 6 A solution of 1 g. of 17u-hydroxy-l7 3-ethynyl-l8- methyl-14p-estr-4-en-3-one in 40 ml. of ethylacetate is moved by filtration through'Celite diatomaceous earth and washed with ethyl acetate and the combined filtrate and washings are evaporated to dryness under reduced pressure, dried and evaporated to dryness to yield 17ahydroxy-1 7fl-vinyl-18-methyl-14;3-estr-4-en-3-one which is I further'purifiedthrough recrystallization from acetone.

Likewise 17a-hydroxy-1-7B-vinyl-14 3-estr-4-en-3-one is obtained in the same fashion from the corresponding 17 3- ethynyl compound.

A suspension of 0.5 g. of 5% palladium-on-carbon catalyst in 50 ml. of methanol is hydrogenated for 3'0 minutes. A solution of 2 g. of flee-hydroxy-l7fl-vinyl-18- methyl-14,8-estr-4-en-3-one in 200 ml. of methanol is.

added and hydrogenated with agitation until the uptake of hydrogen has ceased. The catalyst is removed by filtration and the solution was evaporatedto yield 17a-hydroxy-l75 ethyl-18-methyl-14/3-estr-4-en-3-one which is recrystallized from methylene chloridezhexane for further purification.

In a similar fashion 17a-hydroxy-17 8-ethyl-l4B-estr-4- en-3-one is obtainedfrom the corresponding 17,8-vinyl derivative. 7

" V Example 7 A mixture of- 7 g. of methylene iodide and 3 g. of zinccopper couple in-lS ml. of anhydrous ether is heated at reflux under nitrogenfor 3 hours. The mixture is then cooled and 2 g. of l7u-hydroxy-17B-vinyl-l8-methyl-14fi-estr-4- en-3-one are added. The mixture is allowed to stand at room temperature for 2 hours and is then poured into 200 ml. of 2% aqueous sodiumcarbonate and extracted twice with 100ml. portions of ether. These extracts are dried over sodium sulfate and evaporated under reduced pressure. The residue is held at 0.01 mm. to remove any unreacted methylene iodide and then recrystallized from hexane to yield 1Wit-hydroxy-17,8-cyclopropy1-18-methyl- By utilizing the appropriate 17,3-vinyl starting material in the foregoing procedure, there is similarly obtained 17a-hydroxy-17/3-cyclopropyl-l4B-estr-4-en-3-one.

Example 8 A mixture of 1 g. of 17a-hydroxy-18-methyl-1418-estr- 4-en-3-one, obtained upon treating S-methoxy-lS-methyl- 145-estra-2,5(10)-dien-l7u-o1 with methanolic hydrochloric acid as described in Example 3, 4 ml. of pyridine and 2 ml. of acetic anhydride is allowed to stand at r room temperaturefor 15 hours. The mixture is then poured into ice water and the solid which forms is collected by filtration, washed with water and dried to yield 17a-acetoxy-18-methyl-14,6-estr-4-en-3-one which may be further purified through recrystallization from acetonezhexane.

l7a-acetoxy-14/8-estr-4-en-3-one is obtained in the same fashion from the analogous starting material.

Example 9 Example 10 A mixture of 1 g. of 17a hydroxy-l7/3-ethynyl-l8- methyl-14fi-estr-4-en-3-one, 1 g. of p-toluenesulfonic acid monohydrate, ml. of acetic acid and 25 ml. of acetic anhydride is allowed to stand at room temperature for 24 hours, and then poured into water and stirred. This mixture is then extracted with methylene chloride and these extracts are dried and evaporated to yield 17a-acetoxy-17fi-ethynyl-1S-methyl-14,8-estr-4-en-3-one which is recrystallized from acetone :ether.

17a acetoxy 17,6 ethnyl-14,8-estr-4-en-3-one is obtained in a similar fashion from the corresponding 17cchydroxy compound.

Example 11 Two milliliters of dihydropyranare added to a solution of l g. of 17a-hydroxy-17B-ethynyl-l8-methyl-14B- estr-4-en-3-one in 15 ml. of benzene. About 1 ml. is removed by distillation to remove moisture and 0.4 g. of p-toluenesulfonic acid is added to the cooled solution. This mixture is allowed to stand at room temperature for 4 days, and is then washed with aqueous sodium carbonate solution and water, dried and evaporated. The residue is chromatographed on neutral alumina, eluting with hexane, to yield 17a tetrahydropyranyloxy-17,8- ethynyl-l8-methyl-14B-estr-4-en-3-one which is recrystallized from pentane.

In a similar fashion the following representative compounds are obtained from the cor-responding free 17ahydroxy compounds via the procedure of this example: 1704 tetrahydropyranyloxy 17B ethyny1-14B-estr-en- 3-one; 17a-tetrahydropyranyloxy-18-methyl 145 estr- 4-en-3-one; and 17u-tetrahydropyranyloxy-14,6-estr-4-en- A solution of 1 g. of sodium borohydride in 3 ml. of water is added to an ice-cooled solution of 1 g. of 17ahydroxy-17fl-ethynyl 18 methyl 14,3 estr-4-en-3-one in ml. of methanol and the mixture then allowed to stand for 16 hours at room temperature. The excess reagent is decomposed by addition of acetic acid and the solution is then concentrated to small volume in vacuo and diluted with water. The product is extracted; with ethyl acetate and these extracts are washed with water, dried and evaporated to yield 3/3-17a-dihydroxy 17 3- ethynyl 18 methyl-l4 8-estr-4-ene which may be further purified by recrystallization from acetone:hexane..

Example 13 A mixture of 1 g. of 3p,l7a-dihydroxy-17B-ethynyl-l8- methyl-14fl-estr-4-ene 4 ml. of pyridine and 2 m1. of acetic anhydride is allowed to stand at room temperature for 15 hours. The mixture is then poured into ice .water and the solid which forms is collected by filtration, washed with water and dried to yield 3fl-acetoxy-l7ahydroxy-17,8-ethynyl-l8-methyl-14/8-estr-4-ene which may be further purified through recrystallization from acetone: hexane.

3,8-acetoxy 17a hydroxy 17,3 ethynyl-l4B-estr- 4-ene is obtained in a similar fashion from the corresponding 3fl-hydroxy compound.

Example 14 By treating 3,3-hydroxy 17o: tetrahydropyranyloxy- 18-methyl 14fl-estr-4-ene according to the procedure of Example 13, utilizing hexanoic acid anhydride in place of acetic anhydride, there is obtained 35 hexanoyloxy 17atetrahydropyranyloxy-18-methy1-14/3-estr-4-ene.

3B hex-anoyloxy-l7a-tetrahydropyranyloxy estr- 4-ene is obtained in an analogous fashion.

Example 15 1. Compounds of the formula:

R H I wherein R is hydrogen or methyl;

R is (lower)alkyl, (lower)alkenyl, (l0wer)alkyny1,

halo(lower) alkynyl or cyclopropyl;

R is hydrogen, tetrahydropyranyl or a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; and

R is an oxygen atom or the group in which R is hydrogen, tetrahydropyranyl or a hydrocarbon carboxylic acyl group of less than 12 carbon atoms.

' 2. 14B-estr-4-enes according to claim 1 wherein R is an oxygen atom and R R and R are as therein defined.

3. 14;3-estr-4-enes according to claim 2 wherein R is hydrogen.

4. 14l3-estr-4-enes according to claim 2 wherein R is methyl. I

5. The 14fi-estr-4-ene according to claim 2 wherein R is hydrogen, R is ethyl and R is hydrogen.

6. The 14(3-estr-4-ene according to claim 2 wherein, R is hydrogen, R is ethynyl and R is hydrogen.

7. The 14,6-estr-4-ene according to claim 2 wherein R is hydrogen, R is chloroethynyl and R is hydrogen.

8. The 14fi-estr-4-ene according to claim 2 wherein R is methyl, R is ethyl and R is hydrogen.

9. The 14p-estr-4-ene according to claim 2 wherein R is methyl, R is ethynyl and R is hydrogen.

10. The 14B-estr-4-ene according to claim 2 wherein R is methyl, R is chloroethynyl and R? is hydrogen.

11. 14,8-estr-4-enes according to claim 2 wherein R is hydrogen and R is a hydrocarbon carboxylic acyl group of less than 12 carbon atoms.

12. 14B-estr-4-enes according to claim 2 wherein R is methyl and R is a hydrocarbon carboxylic acyl group of less than 12 carbon atoms.

13. 17a-adamantoyloxy-14/8-estr-4-en-3-one.

14. l7a-adamantoyloxy-18-methy1-14/3-estr-4-en-3-one.

References Cited UNITED STATES PATENTS 2,846,451 8/1958 Sondheimer et al. 260397.3 3,189,528 6/1965 Smith et a1 -51 3,261,852 7/1966 Rapala 260397.4

FOREIGN PATENTS 674,299 6/ 1952 Great Britain.

OTHER REFERENCES Fried et al., J. Amer. Chem. Soc., 83, 4663 and 4664 (1961).

Edgren et al., Steroids, 2, 319-335 (1963), pp. 314, 320, 321 and 329 relied on.

LEWIS GOTTS, Primary Examiner.

T. MESHBESHER, Assistant Examiner. 

1. COMPOUNDS OF THE FORMULA:
 13. 17 A-ADAMANTOYLOXY-14B-ESTR-4-EN-3-ONE. 